Substituted pyrazines and method of preparing the same



Patented Jan. 12, 1954 UNITED STATES PATENT O.FF;ICE

.SUBSIITUTEDPYRAZINES AND METHOD OF IBREPARING THE SAME Sidney R. -'Saifir, River Edge, N. J., assignorto .American 'Cyanamid Company, New York, N. X.,,za corporation oiiMaine "'NolDraWing. vApplication.Llovernberflli,(1949,

, "Serial No. 129,190

08 Claims. lrhe' present invention-n lates to new 'organic compounds. More particularly, it relates toali- "phatic and aromatic "substitutedl hydroXy-Z- keto1j2dihydropyrazines and "methods of preparation "thereof. White (Science.92: 127 (1940)) disclosed that the mold Aspergz'llus '=flavus will readily grow in liquid media yielding filtrates that are definitely "bactericidal for-some gram "negative as well as gram-positive bacteria. The active component "of the filtrates was later called aspergillic acid and was found to have' thechemical structure 1- hydroxy-2-keto-3- (6.)--.isobutyl-6- (3) -sec.- butyl- 1,2-dihydropyrazine.

I have now found that, other substituted l-hy- 'droxy-2-keto pyrazines have bactericidal properties similar to 'asperg'illic acid. These compounds may "be illustrated-by the following general formula:

i which R" is an alkyl or aryl radical .and R is a hydrogen, alkyl or an .aryl radical and R is an alkyl orhydroxamic acid radical.

The compounds of the present invention are, in general, light yellow to white crystalline solids. They are soluble in dilute alkali except where R and R are aryl radicals, give a red color with ferric chloride and produce green copper salts characteristic of hydroxamic acids.

The compounds are prepared byreacting an a1pha,beta-dicarbony1 compound with an aminoalkylhydroxamicacid or aminoalkyldihydroxamic acid. The reaction which takes place may be illustrated by the-following equation:

in which R, R. and R are as previously defined.

The vicinal dicar'bonyl compounds may be compounds such as diacetyl, propionyl acetyl, dipropionyl, benzil and the like.

The aliphatic hydroxamic acids may be compounds such as aminoalondihydroxamic acid, L-leucinehydroxamic acid, DL-isoleucinehydroxamic acid, norleucinehydroxamic acid, alanineisobutyrohydroxamic (Cl. milk-250) 'hydroxamic acid, 'valinehydroxamic acid, alphaamino 'n-butyro'hydroxamic acid, alpha-aminoacid, alpha-amino invalerohydroxamic acid, alpha amino alphamethyl n-butyrohydroxami'c.acid, and the like.

The reaction to produce the compounds of the present invention is carried :out by mixing the intermediates :in a solvent. Although water is preferred there may also be present water mis- :cible solvents such as methanol, ethanol, etc. The reaction is slightly exothermic and proceeds immediately on mixing "the intermediates.

'The reaction will take place readily-at room temperature although a temperatureof from-0 C. to about 100 C. may be used. The reaction is completed in from a few minutes up to 17 hours. The product can generally be recovered by filtration "and purified by recrystallization or vacuum sublimation.

The following'examples willillustratethe process of the present invention is greater detail.

Example 1 Tea solution 010.9. g. of .diacetyl in 10 ccnof water there .is added 1 g. of aminomalondihy- 'droxamic acid. Upon shaking vigorouslygan almost clear solution results whereupon. a separation of a yellow crystalline substance takes place rapidly. The reaction is accompanied bya very small rise in temperature. After allowing to stand for one and one-half hours, the product is filtered and washed with water. The l-hydroxy- 2 keto-'5,6-dimethyl-1,2-dihydropyrazino-3-hy- ,droxamic acid is then purified by recrystalliza- Example 2 A mixture of 8 g. of L-leucinehydroxamic acid, 7.5 g. of diacetyl and 50 cc. of water is shaken for a few minutes whereupon a clear solution results accompanied by a slight evolution of heat. The solution is then allowed to stand at room temperature for two days. A light yellow crystalline solid separates and is filtered. The yield of 1-hydroxy-2-keto-3-isobutyl-5,6-dimethyl-1,2- dihydropyrazine is 4 g., melting point 9698 C. A sample of this material was sublimed at 100- 110 at 0.05 mm. yielding a white crystalline sublimate whichmelted at 68-70 C. On standing overnight the white solid changes to a light yellow solid and melts at 96-98 C. The solids melting at 68-70 C. and at 96-98 C. appear to be dimorphous modifications of the same substance.

Example 3 A mixture of 4.6 g. of DL-isoleucinehydroxamic acid, 4 g. of diacetyl and 15 cc. of water is shaken in a stoppered flask for a few minutes whereupon a clear solution results. Within a few minutes the product begins to crystallize. After standing for two days, it is filtered, washed with water and dried; yield 3.5 g. The l-hydroxy- 2 keto 3 sec. butyl 5,6 dimethyl 1,2- dihydropyrazine obtained has a melting point of Example 4 Example 5 A mixture of 4.2 g. of benzil, 3.45 g. of L-leucine-hydroxamic acid and 100 cc. of 50% ethanol is refluxed seventeen hours and the resulting light brown product is filtered, washed with 1 N hydrochloric acid and recrystallized from benzene. The product is obtained in the form of white needles, having a melting point of 215- 217 C. (dec.). On analysis for carbon, hydrogen and nitrogen the values obtained agreed very closely with the theoretical values for l-hydroxy- 2 keto 3 isobutyl 5,6 diphenyl 1,2-dihydropyrazine.

I claim:

1. 1 hydroxy 2 keto 5,6 dimethyl- 1,2-dihydropyrazino-3-hydroxamic acid.

2. 1 hydroxy 2 keto 3 isobutyl 5,6-

diphenyl- 1,2-dihydropyrazine.

3. A method which comprises mixing together in a solvent a compound having the formula:

in which R and R are lower alkyl radicals and a compound having the formula:

4 in which R is a lower alkyl radical, whereby compounds having the general formula:

in which R, R and R are as defined above, are produced and recovered.

4. A method which comprises reacting together in a substantially aqueous solvent diacetyl and L-leucinehydroxamic acid whereby l-hydroXy 2 keto 3 isobutyl 5,6 dimethyl- 1,2-dihydropyrazine is produced and recovered.

5. A method which comprises reacting together in a substantially aqueous solvent diacetyl and aminomalondihydroxamic acid whereby 1- hydroxy 2 keto 5,6 dimethyl 1,2 dihydropyrazino-3-hydroxamic acid is produced and recovered.

6. A method which comprises reacting togeth er in a substantially aqueous solvent diacetyl and DL-isoleucinehydroxamic acid whereby l-hydroxy 2 keto -'3 sec. butyl 5,6 dimethyl- 1,2-dihydropyrazine is produced and recovered.

7. A 1 hydroxy 2 keto 3 lower alkyl-1,2- dihydropyrazine-5,6-di-monocyclic aromatic hydrocarbon.

8. A method which comprises mixing together in a solvent a compound having the formula:

in which R is a member of the group consisting of lower alkyl and monocyclic aromatic hydrocarbon radicals and R is a member of the group consisting of hydrogen, lower alkyl and monocyclic aromatic hydrocarbon radicals and a compound having the formula:

in which R is a member of the group consisting of lower alkyl and hydroxamic acid radicals whereby compounds having the general formula:

in which R, R and R are as defined above, are produced and recovered. SIDNEY R. SAFIR.

References Cited in the file of this patent J. Am. Chem. Soc., 71 67-70 (1949). 

3. A METHOD WHICH COMPRISES MIXING TOGETHER IN A SOLVENT A COMPOUND HAVING THE FORMULA:
 7. A 1 - HYDROXY - 2 - KETO - 3 - LOWER ALKYL-1,2DIHYDROPYRAZINE-5,6-DI-MONOCYCLIC AROMATIC HYDROCARBON. 